title: MiR-218 suppresses nasopharyngeal cancer progression through downregulation of survivin and the SLIT2-ROBO1 pathway.
abstract: Nasopharayngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy most common in East Asia and Africa. Here we report frequent downregulation of the microRNA miR-218 in primary NPC tissues and cell lines where it plays a critical role in NPC progression. Suppression of miR-218 was associated with epigenetic silencing of SLIT2 and SLIT3, ligands of ROBO receptors that have been previously implicated in tumor angiogenesis. Exogenous expression of miR-218 caused significant toxicity in NPC cells in vitro and delayed tumor growth in vivo. We used an integrated trimodality approach to identify targets of miR-218 in NPC, cervical, and breast cell lines. Direct interaction between miR-218 and the 3'-untranslated regions (UTR) of mRNAs encoding ROBO1, survivin (BIRC5), and connexin43 (GJA1) was validated in a luciferase-based transcription reporter assay. Mechanistic investigations revealed a negative feedback loop wherein miR-218 regulates NPC cell migration via the SLIT-ROBO pathway. Pleotropic effects of miR-218 on NPC survival and migration were rescued by enforced expression of miR-218-resistant, engineered isoforms of survivin and ROBO1, respectively. In clinical specimens of NPC (n=71), ROBO1 overexpression was significantly associated with worse overall (P=0.04, HR=2.4) and nodal relapse-free survival (P=0.008, HR=6.0). Our findings define an integrative tumor suppressor function for miR-218 in NPC and further suggest that restoring miR-218 expression in NPC might be useful for its clinical management.
authors.affiliation: Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Nehad M
authors.initials: NM
authors.lastname: Alajez
authors.forename: Michelle
authors.initials: M
authors.lastname: Lenarduzzi
authors.forename: Emma
authors.initials: E
authors.lastname: Ito
authors.forename: Angela B Y
authors.initials: AB
authors.lastname: Hui
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Jeff
authors.initials: J
authors.lastname: Bruce
authors.forename: Shijun
authors.initials: S
authors.lastname: Yue
authors.forename: Shao H
authors.initials: SH
authors.lastname: Huang
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: John
authors.initials: J
authors.lastname: Waldron
authors.forename: Brian
authors.initials: B
authors.lastname: O'Sullivan
authors.forename: Fei-Fei
authors.initials: FF
authors.lastname: Liu
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000368:Aged; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D045744:Cell Line, Tumor; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000077022:Survivin; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
chemical_list: D020413:3' Untranslated Regions; D001374:Azacitidine; D018031:Connexin 43; D000077209:Decitabine; D051034:Inhibitor of Apoptosis Proteins; D036341:Intercellular Signaling Peptides and Proteins; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D000077022:Survivin; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein; C107489:BIRC5 protein, human; C500216:GJA1 protein, human; C547471:MIRN218 microRNA, human